1 12 February 2024

2 EMA/CHMP/20607/2024
3 Committee for Medicinal Products for Human Use (CHMP)

4 Guideline on the pharmaceutical quality of inhalation and

5 nasal medicinal products
6 Draft

Draft agreed by Quality Working Party 16 January 2024

Adopted by CHMP for release for consultation

12 February 2024

Start of public consultation 12 April 2024

End of consultation (deadline for comments) 31 October 2024

7
8 This guideline replaces the guideline on pharmaceutical quality of inhalation and nasal products
9 (EMEA/CHMP/QWP/49313/2005 Corr) and Quality of medicines questions and answers: Part 2 Specific
10 type of products – Dry product inhalers; Orally inhaled products; Storage – What are the requirements
11 for storage orientation recommendations in the product information for pressurised metered dose
12 inhalers.
13
Comments should be provided using this EUSurvey form. For any technical issues, please contact
the EUSurvey Support.

14
Keywords Inhalation medicinal products, nasal medicinal products, pharmaceutical
quality, pressurised metered-dose inhalers (pMDI), dry powder inhalers (DPI),
medicinal products for nebulisation, non-pressurised metered-dose inhalers,
nasal sprays, nasal powders, nasal liquids

15

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© European Medicines Agency, 2024. Reproduction is authorised provided the source is acknowledged.
16 Guideline on the pharmaceutical quality of inhalation and
17 nasal medicinal products
18 Table of contents
19 Executive summary ..................................................................................... 3
20 1. Introduction (background) ...................................................................... 3
21 2. Scope....................................................................................................... 3
22 3. Legal basis and relevant guidelines ......................................................... 3
23 4. Inhalation products ................................................................................. 4
24 4.1. Active substance (CTD 3.2.S) ................................................................................ 4
25 4.2. Finished medicinal product (CTD 3.2.P) ................................................................... 4
26 4.2.1. Description and composition of the finished medicinal product (CTD 3.2.P.1) ............ 4
27 4.2.2. Pharmaceutical development (CTD 3.2.P.2) .......................................................... 5
28 4.2.3. Manufacture (CTD 3.2.P.3) ............................................................................... 13
29 4.2.4. Control of excipients (CTD 3.2.P.4) .................................................................... 14
30 4.2.5. Control of the finished medicinal product (CTD 3.2.P.5) ........................................ 15
31 4.2.6. Container Closure System (CTD 3.2.P.7, 3.2.R) ................................................... 18
32 4.2.7. Stability (CTD 3.2.P.8) ..................................................................................... 19
33 4.3. Therapeutic equivalence ...................................................................................... 19
34 4.4. Product information ............................................................................................ 20
35 4.5. Lifecycle management ........................................................................................ 21

36 5. Nasal products....................................................................................... 21
37 5.1. Active substance (CTD 3.2.S) .............................................................................. 21
38 5.2. Finished medicinalproduct (CTD 3.2.P) .................................................................. 22
39 5.2.1. Description and composition of the finished medicinal product (CTD 3.2.P.1) .......... 22
40 5.2.2. Pharmaceutical development (CTD 3.2.P.2) ........................................................ 22
41 5.2.3. Manufacture (CTD 3.2.P.3) ............................................................................... 24
42 5.2.4. Control of excipients (CTD 3.2.P.4) .................................................................... 24
43 5.2.5. Control of the finished product (CTD 3.2.P.5) ...................................................... 25
44 5.2.6. Container closure system (CTD 3.2.P.7) ............................................................. 26
45 5.2.7. Stability (CTD 3.2.P.8) ..................................................................................... 26
46 5.3. Therapeutic equivalence ...................................................................................... 26
47 5.4. Product information ............................................................................................ 27
48 5.5. Lifecycle management ........................................................................................ 28

49 Definitions ................................................................................................. 29
50
51

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52 Executive summary
53 This guideline is the first revision of the guideline on pharmaceutical quality of inhalation and nasal
54 products (EMEA/CHMP/QWP/49313/2005 Corr). The main aim of the first revision is to consolidate the
55 information available in the previous guidance documents, the related published questions and
56 answers, also taking into consideration recent advancements in the field, common practice and new
57 regulations, including the medical device regulation. Requirements for demonstration of therapeutic
58 equivalence for orally inhaled products (OIP) are included in the Guideline on the requirements for
59 demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and chronic
60 obstructive pulmonary disease (COPD). These two guidelines are complementary and should be read in
61 conjunction to each other.

62 1. Introduction (background)
63 This guideline concerns the quality aspects of human medicinal products intended for delivery of active
64 substance(s) into the lungs or to the nasal mucosa with the purpose of evoking a local or systemic
65 effect. Quality aspects specific to inhalation and nasal medicinal products are discussed, the need for
66 safety testing (e.g., for excipients and leachables) is also considered. Additional quality aspects (e.g.,
67 impurities, process validation, stability testing, specifications) as well as safety and efficacy aspects are
68 described in other guidance documents, including ICH guidelines.

69 Detailed guidance on pharmaceutical development study designs (e.g., priming studies) and the
70 analytical procedures primarily used for inhalation and nasal medicinal products (e.g., cascade
71 impactor analysis) is not included in this guideline. This information may be found in other publications
72 (e.g., European Pharmacopoeia).

73 2. Scope
74 The guideline addresses requirements "on the quality of inhalation and nasal medicinal products" in
75 new marketing authorisation applications, including abridged applications. The general principles
76 described in this guideline should also be considered when making changes to authorised medicinal
77 products and during development of medicinal products used in clinical trials. It is not expected that all
78 described testing would be conducted on all clinical trial batches. However, extensive characterisation
79 of the active substance and finished medicinal product batches used in pivotal clinical trials is
80 necessary to qualify the medicinal product proposed for marketing.

81 This guideline has been developed for medicinal products containing active substances of synthetic or
82 semi-synthetic origin. However, the general principles described should also be considered for other
83 inhalation and nasal medicinal products with active substances of other origins.

84 The guideline applies to medicinal products developed for administration of active substance(s) to the
85 lungs, such as pressurised and non-pressurised metered-dose inhalers (MDI), dry powder inhalers
86 (DPI), medicinal products for nebulisation, as well as pressurised metered-dose nasal sprays, nasal
87 powders and nasal liquids. Liquid inhalation anaesthetics and nasal ointments, creams and gels are
88 excluded, however the general principles described in this guideline should be considered.

89 3. Legal basis and relevant guidelines

90 This Guideline should be read in conjunction with the introduction and general principles of Annex I to
91 Directive 2001/83/EC, as amended, and all other relevant EU and ICH guidelines. These include, but
92 are not limited to:

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 93 • Regulation (EU) 2017/745 on Medical Devices,

94 • Guideline on the requirements for demonstrating therapeutic equivalence between orally

95 inhaled products (OIP) for asthma and chronic obstructive pulmonary disease (COPD)
96 (CPMP/EWP/4151/00 Rev. 1),

97 • Guideline on quality documentation for medicinal products when used with a medical device
98 (EMA/CHMP/QWP/BWP/259165/2019) and the related Q&As on the implementation of the
99 Medical Device Regulation,

100 • Questions and answers on data requirements when replacing hydrofluorocarbons as propellants
101 in oral pressurised metered dose inhalers (EMA/CHMP/83033/2023),

102 • European Pharmacopeia.

103

104 4. Inhalation medicinal products

105 4.1. Active substance (CTD 3.2.S)

106 For all inhalation finished medicinal products containing an active substance that is not dissolved at
107 any time during the finished product manufacture, storage or use, the particle size of that active
108 substance is a critical parameter. A complete description of the micronisation process and the in-
109 process controls should be provided. Sufficient details need to be included in Module 3.2.S and
110 referenced in Module 3.2.P.2, to assure the required quality of the micronised active substance.

111 The active substance specification should include a test for particle size and specified acceptance
112 criteria. A validated particle sizing method (e.g., laser diffraction), with acceptance criteria set at
113 multiple points across the particle size distribution, should be employed. Acceptance criteria should
114 assure a consistent particle size distribution in terms of the percentage of total particles in given size
115 ranges. The median, upper and/or lower particle size limits should be well-defined. Acceptance criteria
116 should be set based on the observed range of variation and should take into account the particle size
117 distribution of batches that showed acceptable performance in vivo.

118 Different polymorphic forms including any amorphous content could affect the quality or performance
119 of the finished medicinal product. If relevant, the appropriate solid-state form should be specified and
120 controlled in accordance with ICH Q6A.

121 Control of microbiological quality should be considered where applicable.

122 If alternative sources of the active substance are proposed, evidence of equivalence should include
123 appropriate physical characterisation and in vitro performance studies (see section 4.2.2
124 Pharmaceutical Development).

125 4.2. Finished medicinal product (CTD 3.2.P)

126 4.2.1. Description and composition of the finished medicinal product (CTD
127 3.2.P.1)

128 The complete qualitative and quantitative composition should be specified including any excipient (e.g.,
129 solvents, gasses) removed during manufacturing. The amount of each active substance and excipient
130 should be expressed in concentration (i.e., amount per unit volume or weight), total amount per
131 container and amount per actuation should be defined both as metered and delivered dose.

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132 The primary packaging, type of inhaler and, if necessary, the secondary packaging or other
133 components required for reasons of stability should be described. A detailed description of the
134 packaging should be included in Module 3.2.P.7.

135 4.2.2. Pharmaceutical development (CTD 3.2.P.2)

136 Pharmaceutical development studies are conducted to demonstrate that the type of formulation along
137 with the pharmaceutical form, manufacturing process, container closure system, microbiological
138 attributes are appropriate and result in acceptable product performance for the target patient
139 population. The development should ensure that the labelled delivered dose is administered in a
140 reproducible and accurate manner. The pharmaceutical development should include usability studies to
141 cover how the finished medicinal product should be used.

142 Quality by Design (QbD) may be used as a development tool. The development studies should be
143 conducted on more than one batch, to account for both inter/intra batch variability, and it is
144 recommended to include a minimum of three batches with at least ten inhalers from each batch. The
145 development batches should be representative of the commercial medicinal product; however, pilot
146 scale batches may be acceptable. In the case of multiple strengths and multiple package sizes (i.e.,
147 number of doses in each inhaler), a justified bracketing and/or matrixing design among the different
148 strengths and/or pack sizes may be used.

149 Sufficient data should be provided to support the proposed specification or to give adequate assurance
150 that those performance characteristics which may not be routinely tested (e.g., priming and testing to
151 exhaustion) have been adequately investigated. All batches used in pivotal clinical studies should be
152 sufficiently characterised to support the specification for the finished medicinal product.

153 The tests indicated in Table 4.2.1 are normally conducted to characterise inhalation medicinal
154 products. Not all tests are necessary for all types of inhalation medicinal products. If the tests
155 described are not conducted due to the particular nature of the finished medicinal product or because
156 assurance of the parameter has been established by other means, a justification for the omission
157 should be provided. Any of the development tests may be applicable to any pharmaceutical form,
158 depending on the instructions for use in the package leaflet (e.g., shaking tests for certain DPI).
159 Moreover, depending on the operational characteristics of the delivery device, additional studies
160 relevant to the performance of the finished medicinal product may be necessary.

Table 4.2.1. Pharmaceutical development studies for inhalation medicinal products.

Pressurised Dry powder Preparations for Non-

metered- inhalers (DPI) nebulisation pressurised
Pharmaceutical
dose metered-
development study Device- Pre- Single- Multi-
inhalers dose
(pMDI) metered metered dose dose inhalers

(a) Physical
Yesa Yes Yes Yesa Yesa Yesa
characterisation

(b) Minimum fill

Yes Yes Yes Yes Yes Yes
justification

(c) Extractable
No No No Yes No No
volume

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 Table 4.2.1. Pharmaceutical development studies for inhalation medicinal products.

Pressurised Dry powder Preparations for Non-

metered- inhalers (DPI) nebulisation pressurised
Pharmaceutical
dose metered-
development study Device- Pre- Single- Multi-
inhalers dose
(pMDI) metered metered dose dose inhalers

(d) Extractables /
Yes No No Yes Yes Yes
leachables

(e) Single-dose fine

Yes Yes Yes No No Yes
particle dose

(f) Aerodynamic
particle / droplet size Yes Yes Yes Yes Yes Yes
distribution

(g) Uniformity of
delivered dose and
Yes Yes Yes No No Yes
fine particle dose
through container life

(h) Uniformity of
delivered dose and
fine particle dose No Yes Yes No No No
over patient flow rate
range

(i) Aerodynamic
particle size
Yes No No No No No
distribution with
spacer use

(j) Actuator /
mouthpiece Yes Yes Yes No No Yes
deposition

(k) Delivery rate and

No No No Yes Yes No
total delivered dose

(l) Shaking
Yesa No No Yesa Yesa Yesa
requirements

(m,n) Initial & re-

Yes No No No No Yes
priming requirements

(o) Cleaning
Yes Yes Yes No No Yes
requirements

(p) Low temperature

Yes No No No No No
performance

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 Table 4.2.1. Pharmaceutical development studies for inhalation medicinal products.

Pressurised Dry powder Preparations for Non-

metered- inhalers (DPI) nebulisation pressurised
Pharmaceutical
dose metered-
development study Device- Pre- Single- Multi-
inhalers dose
(pMDI) metered metered dose dose inhalers

(q) Performance
after temperature Yes No No No No Yes
cycling

(r) Effect of
environmental Yes Yes Yes No No No
moisture

(s) Robustness Yes Yes Yes No No Yes

(t) Delivery device

Yes Yes Yes Yes Yes Yes
development

(u) Preservative
effectiveness / No No No Yesb Yesb Yesb
efficacy

(v) Compatibility No No No Yes Yes No

(x) Spray pattern /

Yes No No No No Yes
plume geometry

161 aFor suspensions.

162 bIf a preservative is present.

163 4.2.2.1. (a) Physical characterisation (CTD 3.2.P.2.1.1 and 3.2.P.2.1.2)

164 Physical characteristics of the active substance(s) and excipients such as solubility, particle size,
165 particle shape, density, rugosity, charge, polymorphic form and crystallinity may influence the
166 homogeneity, reproducibility and performance of the finished medicinal product. Development studies
167 should include the physical characterisation of the active substance(s) and excipients relevant to their
168 effect on the performance of the finished medicinal product.

169 If applicable, the effect of pre-processing (e.g., micronisation) active substance(s) and/or excipient(s)
170 on the physical properties should be evaluated and reported, including storage conditions and time for
171 conditioning of the ingredients. Relevant information on the development of the micronisation process
172 itself should be included.

173 For the finished medicinal product, development and characterisation studies based on dissolution
174 testing can be provided as supportive information.

175 4.2.2.2. (b) Minimum fill justification (CTD 3.2.P.2.2.2)

176 For MDIs and device-metered DPIs, a study should be conducted to demonstrate that the individual
177 container minimum fill, as defined by the finished medicinal product manufacturing process, is
178 sufficient to provide the number of actuations on the product information. The last doses delivered by

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179 the inhaler as defined by the label claim, should meet the finished medicinal product specification limits
180 for delivered dose and fine particle dose.

181 For pre-metered DPI and medicinal products for nebulisation, the fill volume and/or weight should be
182 justified by demonstrating acceptable uniformity of delivered dose and fine particle dose throughout
183 the defined fill volume range.

184 4.2.2.3. (c) Extractable volume (CTD 3.2.P.2.2.2)

185 The extractable volume may differ from the fill volume due to retaining of the finished medicinal
186 product in the container closure system and may depend on the materials and shape/dimensions of the
187 container.

188 4.2.2.4. (d) Extractables / leachables (CTD 3.2.P.2.4)

189 For compendial plastic materials a reference to the relevant European pharmacopoeial monograph, or
190 the monograph of a member state should be provided. The leachables profile should be determined for
191 plastic container closure components, in line with guidance.

192 For non-compendial plastic materials, rubber container closure components and any other relevant
193 components that are in contact with the formulation during storage (e.g., valves and oil and lubricants
194 used in the valve), a study should be conducted to determine the extractables profile even when the
195 material is approved for use in food packaging. The principles described in relevant guidelines (e.g.,
196 CPMP/QWP/4359/03 Guideline on plastic immediate packaging materials) should be taken into
197 account. Details and justification of the study design (e.g., solvents used, temperature, storage time)
198 and the results should be provided. It should be determined whether any of the extractables are also
199 leachables present in the formulation at the end of the shelf-life of the medicinal product or to the
200 point equilibrium is reached, if sooner.

201 For compounds that appear as leachables, identification should be attempted, and safety assessments
202 should be conducted in accordance with adequately established safety thresholds. A cross-reference to
203 the data presented in Module 4 (Safety) should be included. Safety risk assessment principles for
204 limiting potential carcinogenic risk as outlined in ICH M7 should be used. If applicable a tabulated list
205 of potential genotoxic substances and their acceptability in respect to safety concerns should be
206 provided. If there are no safety concerns with the type and level of leachables detected, routine
207 monitoring of leachables would not be necessary. The use of components potentially leaching
208 compounds with structural alerts belonging to the cohort of concern should be avoided.

209 Depending on the levels and types of compounds detected, consideration should be given to include a
210 test and limits for leachables in the finished medicinal product specification. If a correlation between
211 extractable and leachable profiles can be established, control of leachables could be accomplished via
212 testing and limits of extractables on the components.

213 4.2.2.5. (e) Single-dose fine particle dose (CTD 3.2.P.2.4)

214 The fine particle dose should be routinely determined using the minimum number of actuations in the
215 recommended dose specified in the product information, if technically possible. If the fine particle dose
216 test included in the finished medicinal product specification uses a sample size greater than the
217 minimum number of actuations, a study should be conducted to demonstrate that the sample size
218 used routinely provides results comparable to those obtained using the minimum number of
219 actuations. The amount deposited on each stage of the cascade impactor should be sufficient for a
220 reliable assay, but not too excessive to bias the results by masking individual actuation variability.
221 Justification for not conducting this test (e.g., for low dosed medicinal products) should be provided.

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222 The fine particle dose of the minimum number of actuations in the recommended dose should be
223 determined according to the finished medicinal product specification fine particle dose method,
224 modified only as necessary to accommodate the reduced sample size. If this study is not feasible due
225 to the sensitivity of the analytical method, data supporting this claim should be provided.

226 4.2.2.6. (f) Aerodynamic particle / droplet size distribution (CTD 3.2.P.2.4)

227 The aerodynamic particle size distribution (APSD) is considered as one of the Critical Quality Attributes
228 (CQA) of inhalation medicinal products. It is therefore important to fully characterise the APSD during
229 the development to ensure consistency with the commercial medicinal product.

230 To allow an assessment of the complete profile of the medicinal product used for in vivo studies
231 (pivotal clinical and/or comparative), individual stage particle size distribution data should be provided
232 for the batches used in these studies, as well as data on batches representative of the commercial
233 process. Any differences between the commercial and clinical batches should be explained and
234 justified.

235 Using a multistage impactor or impinger, the mass of the active substance(s) on each stage and the
236 cumulative mass undersize, at a given stage, should be determined instead of the percentage of the
237 emitted dose as these can hide variations in delivered dose. A plot of cumulative percentage less than
238 a stated cut-off diameter versus cut-off diameter should usually be provided. From this, the Mass
239 Median Aerodynamic Diameter (MMAD) and Geometric Standard Deviation (GSD) may be determined,
240 if appropriate (in the case of uni-modal log-normal distribution). Mass balance reconciliation should
241 also be considered.

242 When a range of different strengths is proposed proportionality in APSD or group of stages should be
243 determined and evaluated for clinical impact.

244 For solutions for nebulisation droplet size distribution may be tested by other methods than cascade
245 impactor (e.g., laser diffraction if cross-validated against a cascade impaction method).

246 4.2.2.7. (g) Uniformity of delivered dose and fine particle dose through container life (CTD
247 3.2.P.2.4)

248 A study should be conducted to demonstrate the consistency of the delivered dose and the fine particle
249 dose through the life of the container from the first dose (post-priming for products with priming
250 instructions) until the last labelled dose. The study should be performed using the minimum
251 recommended dose as stated in the product information (i.e., one or more actuations). The containers
252 should be used and tested according to the instructions given in the package leaflet with respect to
253 storage orientation and cleaning requirements, as well as the minimum dosing interval. For MDIs,
254 pressurised and non-pressurised, and for device-metered DPI at least ten doses from the combination
255 of the beginning, middle and end of a single container should be tested. For pre-metered DPI ten doses
256 should be tested.

257 The doses should meet the finished medicinal product specification limits for uniformity of delivered
258 dose and fine particle dose. Non-conforming results should be explained.

259 The doses between the last labelled dose and the last container exhaustion dose should also be tested
260 and information on the tail-off profile should be provided where applicable. This testing may be waived
261 if the container contains a lockout mechanism that prevents dosing beyond the labelled number of
262 doses.

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263 4.2.2.8. (h) Uniformity of delivered dose and fine particle dose over patient flow rate range
264 (CTD 3.2.P.2.4)

265 A study should be conducted to demonstrate the consistency of the delivered dose and the fine particle
266 dose over a range of flow rates (through the delivery device) covering the inspiratory effort of the
267 intended patient population. Using three fixed flow rates in a range of about 30-90 L/min is typically
268 acceptable.

269 4.2.2.9. (i) Aerodynamic particle size distribution and delivered dose with spacer/holding
270 chamber use (CTD 3.2.P.2.4)

271 For inhalation medicinal products that may be administered with a spacer or holding chamber, studies
272 should be conducted to determine to what extent the use of the spacer or holding chamber changes
273 the aerodynamic particle size distribution (APSD) and the delivered dose. If the instructions
274 accompanying the spacer or holding chamber include an in-use cleaning schedule (e.g., weekly
275 cleaning), the APSD should be tested before and after cleaning the spacer or holding chamber
276 according to the instructions provided with the device. Differences in APSD when using spacer or
277 holding chamber could impact the therapeutic equivalence, hence clinical studies might be needed
278 (CPMP/EWP/4151/00 Guideline on the requirements for demonstrating therapeutic equivalence
279 between orally inhaled products (OIP) for asthma and chronic obstructive pulmonary disease (COPD)).

280 The testing of APSD and delivered dose may be altered, to mimic patient performance with the spacer
281 or holding chamber (e.g., a 2 second delay for APSD by a multistage cascade impactor, tidal breathing
282 for delivered dose). To reduce variability, the potential impact of external factors should be taken into
283 considerations. As an example, special precautions such as earthing of the spacer and handling of the
284 test equipment are required for minimising the impact of electrostatic interference.

285 4.2.2.10. (j) Actuator / mouthpiece deposition (CTD 3.2.P.2.4)

286 The amount of active substance(s) deposited on the actuator or mouthpiece should be determined and,
287 where applicable, demonstrated to be consistent with any correction factor used to support ex-valve
288 (or ex-delivery device) label claims.

289 4.2.2.11. (k) Delivery rate and total delivered dose (CTD 3.2.P.2.4)

290 To allow an assessment of the complete delivery profile of the medicinal product used for in vivo
291 studies (pivotal clinical and/or comparative) or in vitro characterisation and/or comparative studies,
292 the active substance(s) delivery rate and total active substance delivered should be provided. A
293 validated method (e.g., breath simulator) should be employed. The aerosol should be generated with
294 the nebuliser system(s) and settings used in the in vivo studies or comparative in vitro studies.

295 4.2.2.12. (l) Shaking requirements (CTD 3.2.P.2.4)

296 For finished medicinal products that according to the instructions given in the package leaflet, require
297 shaking before use, a study should be conducted to demonstrate that the shaking instructions are
298 adequate. The possibility of shaking leading to inaccurate dosing (e.g., due to foaming) or other
299 changes in product performance should be examined by testing the delivered dose uniformity.

300 4.2.2.13. (m) Initial priming of the container (CTD 3.2.P.2.4)

301 A study should be conducted to support the number of actuations that should be fired to waste
302 (priming actuations) prior to the patient using the medicinal product for the first time. Containers
303 should be stored in various orientations prior to the initiation of the study in order to account for the

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304 different storage orientations likely to occur in real life settings. The length of storage prior to
305 conducting the study should be indicated and justified. If storage orientation has a significant effect on
306 the delivered dose a storage orientation recommendation should be added in the product information.

307 The number of priming actuations required until the subsequent doses meet the finished medicinal
308 product specification limits for delivered dose uniformity should be determined.

309 Priming instructions should be provided in the product information.

310 4.2.2.14. (n) Re-priming of the container following storage (CTD 3.2.P.2.4)

311 A study should be conducted to support the length of time that the finished medicinal product may be
312 stored without being used (after initial priming) before re-priming is needed. Multiple time points
313 should be investigated and containers should be stored in various orientations prior to, and during the
314 study, in order to determine the effect of orientation. The need to test products at different stages
315 through container life should also be considered. The number of re-priming actuations required until
316 the subsequent doses meet the finished medicinal product specification limits for delivered dose
317 uniformity should be determined.

318 Re-priming instructions, including the length of storage after which re-priming should be performed,
319 the number of re-priming actuations required and any necessary instructions with respect to storage
320 orientation, should be provided in the product information. The instructions must be confirmed by
321 user-acceptance testing. As it cannot be guaranteed that the medicinal product always is stored in the
322 preferred orientation, the re-priming instructions should be based on the worst-case scenario (i.e., the
323 orientation which requires the shortest re-priming period or the highest number of re-priming
324 actuations).

325 4.2.2.15. (o) Cleaning requirements (CTD 3.2.P.2.4)

326 Delivered dose uniformity and fine particle dose or droplet size distribution data should be provided to
327 support the recommended cleaning instructions in the product information, including method and
328 frequency. The study should be conducted under conditions of normal patient usage, in accordance
329 with recommendations for priming, dosing intervals and typical dosing regimen.

330 If the device is designed to have the mouthpiece removed for periodic cleaning, testing should be
331 performed in accordance with the instructions given in the labelling, and as a worst case without
332 removal and cleaning.

333 This study could be combined with 4.2.2.7 (Uniformity of delivered dose and fine particle dose through
334 container life).

335 4.2.2.16. (p) Low temperature performance (CTD 3.2.P.2.4)

336 A study should be conducted to determine the effect of low temperature storage on the performance of
337 the product. Containers should be stored in various orientations for at least 3 hours at a temperature
338 below freezing (0°C), and then immediately tested.

339 The number of actuations required until the subsequent doses meet the finished medicinal product
340 specification limits for delivered dose uniformity and fine particle dose should be determined. If the
341 product does not perform satisfactorily (e.g., re-priming actuations required exceed the number
342 required according to the instructions for use), an additional study should be conducted to determine
343 the method and length of time needed to adequately warm the containers so that satisfactory
344 performance is achieved.

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345 Instructions regarding cold temperature use should be provided in the product information. If this
346 study is not conducted, information on how and how long to warm the container should be provided.
347 Alternative approaches for inhalation medicinal products which do not tolerate low temperatures should
348 be fully justified.

349 4.2.2.17. (q) Performance after temperature cycling (CTD 3.2.P.2.4)

350 The effect of temperature cycling on the performance of the product should be evaluated. A study
351 should be conducted for 3-4 weeks using containers stored in various orientations and cycled between
352 one temperature below freezing (-10 to -20°C) and one above room temperature (40°C). Storage time
353 should be at least 12 hours under each condition. Alternative conditions and durations can be used, if
354 justified.

355 The containers should be examined visually for any obvious defects, and tests such as leak rate,
356 weight loss, delivered dose uniformity, fine particle dose, related substances and moisture content
357 should be performed. Any changes from initial results should be assessed for their significance.

358 4.2.2.18. (r) Effect of environmental moisture (CTD 3.2.P.2.4)

359 The effect of environmental moisture on product performance of unprotected finished medicinal
360 product should be investigated during development. The propellant in pMDIs may have a high affinity
361 for water. The APSD of DPIs may be impacted by moisture. In view of the potential impact of
362 environmental moisture and temperature on the performance of the finished medicinal product, studies
363 at 25°C/70% RH are expected, as a minimum. For pre-metered products using capsules, special
364 attention should be paid to brittleness of the capsules under various humidity conditions, and
365 therefore, studies at lower humidity (e.g., 35% RH or 40% RH) are also expected.

366 4.2.2.19. (s) Robustness (CTD 3.2.P.2.4)

367 The product performance should be investigated under conditions to simulate patient use. This includes
368 activating the delivery device at the frequency indicated in the product information. Carrying the
369 delivery device between use, simulation of dropping the delivery device and the robustness of any
370 lockout mechanism, digital sensor etc., should be considered.

371 Vibrational stability of powder mixtures should be demonstrated in order to simulate vibrations during
372 transport and use. Significant variations in the delivered dose and/or fine particle dose should be fully
373 discussed in terms of the safety and efficacy of the medicinal product.

374 Dropping of the device should be investigated. The dropping simulation should be performed towards
375 the end of the life of the product (e.g., at dose 180 for a 200 doses product) in order to assess the
376 effect of finished medicinal product accumulated on the mouthpiece, or any other part of the device,
377 during the life-time of the device. Significant variations in the delivered dose and/or fine particle dose
378 should be discussed in terms of the safety and efficacy of the medicinal product. Appropriate handling
379 instructions should be established based on the results obtained and included in the product
380 information.

381 4.2.2.20. (t) Delivery device development (CTD 3.2.P.2.4 and 3.2.R)

382 The development of the delivery device should be described. Any changes implemented in the design
383 (e.g., change of component materials) and/or manufacturing process of the delivery device (e.g., scale
384 up from single cavity to multiple cavity tooling) during the development of the medicinal product
385 should be discussed in terms of the impact on the product performance characteristics (e.g., delivered
386 dose, fine particle dose). If prototype delivery devices were used in clinical studies, their equivalence

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387 with the delivery device intended for marketing should be demonstrated by providing equivalence
388 performance data.

389 For DPI, safeguards to prevent inadvertent multiple dose metering (and subsequent inhalation by the
390 patient) should be demonstrated.

391 For breath-actuated delivery devices, data should be provided to demonstrate that the target patient
392 groups are capable of triggering the delivery device. Unless this aspect is covered by clinical data,
393 dedicated patient usability studies may be warranted. The triggering mechanism should be well
394 characterised as part of the delivery device development programme.

395 For multidose inhalation medicinal products each unit should have a dose counter to give the patient
396 indication of when the number of actuations stated on the label has been delivered.

397 4.2.2.21. (u) Preservative effectiveness / efficacy (CTD 3.2.P.2.5)

398 For medicinal products containing a preservative a study should be conducted to demonstrate the need
399 and effectiveness/efficacy of the preservative.

400 4.2.2.22. (v) Compatibility (CTD 3.2.P.2.6)

401 If the medicinal product is to be diluted prior to administration compatibility should be demonstrated
402 with all diluents over the range of dilution proposed in the product information. These studies should
403 preferably be conducted on aged samples and should cover the duration of storage of the diluted
404 medicinal product indicated in the product information. Where the product information specifies co-
405 administration with other medicinal products, compatibility with all the finished medicinal products
406 should be demonstrated.

407 Parameters such as precipitation, pH, droplet size distribution, delivery rate and delivered dose should
408 be tested and differences from the concentrated product should be assessed for their significance.

409 4.2.2.23. (x) Spray pattern / plume geometry (CTD 3.2.P.2.4)

410 Spray pattern and plume geometry should be studied where appropriate to characterise the
411 performance of the complete finished medicinal product, i.e., the formulation in combination with the
412 pump.

413 4.2.3. Manufacture (CTD 3.2.P.3)

414 A detailed description of the manufacturing process for the finished medicinal product, including filling
415 and packaging, should be included. If the active substance or any excipient is micronised after being
416 received from the supplier, the micronisation process should be described. Any conditioning of DPIs or
417 equilibration time allowed for pressurised medicinal products, before release testing, should be
418 specified and justified along with other aspects of the manufacturing process.

419 Inhalation medicinal products, in particular DPI and pMDI, are considered specialised dosage forms
420 manufactured by non-standard manufacturing processes. Module 3.2.P.3.3 and 3.2.P.3.4 should be
421 sufficiently detailed and include both critical and non-critical process parameters justified by reference
422 to the manufacturing process development undertaken.

423 The controls for critical steps and intermediates should be described. Appropriate in-process controls
424 should be established based on the CQAs and Critical Process Parameters (CPPs) determined during
425 the development studies, e.g., performance testing of the actuation release mechanism (shot weight)
426 of each unit, homogeneity of the formulation.

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427 The manufacturing process should be validated to ensure the homogeneity of the formulation
428 throughout the filling process during routine production and include controls assuring that all
429 containers are within an appropriate fill volume or fill weight range and that the closure system is
430 applied correctly (e.g., crimp dimensions and leak testing for pressurised inhalers, blister sealing for
431 DPI). The yield of the assembling step of the validation batches should be reported and discussed to
432 ensure a robust process. The scale of manufacture should be supported by process validation batch
433 data at the proposed production scale. Exemptions may be accepted if adequately justified as
434 described in the guideline on process validation (EMA/CHMP/CVMP/QWP/BWP/70278/2012 Rev 1 Corr
435 1).

436 4.2.4. Control of excipients (CTD 3.2.P.4)

437 For most inhalation medicinal products, excipients (when used) comprise a significant part of the
438 formulation content by weight and thereby may have a substantial effect on safety, quality and
439 performance of the medicinal product. Besides pharmacopoeial requirements additional functionality-
440 related tests should be included in the specifications as appropriate. For all excipients specifications
441 should be set in consideration of their impact on the finished medicinal product CQAs, as justified
442 during finished medicinal product development.

443 For DPI, a suitable multi-point particle size test should be included for the excipient(s) (e.g., lactose)
444 or where appropriate for granules of excipients and/or the active substance(s). The limits for this test
445 should be qualified by the results of batches used in the in vivo studies (pivotal clinical and/or
446 comparative), although in vitro data (from multistage impaction/impinger) may suffice to demonstrate
447 the suitability of the extremes of the limits.

448 Control of microbiological quality should be considered and where applicable justification provided for
449 not conducting routine microbiological quality control tests.

450 Control of physical parameters may be achieved by specification of the grade of each material used.
451 For excipients which have physical properties that cannot be easily controlled but are relevant for the
452 finished medicinal product performance (e.g., morphology of particles, viscosity number), it may be
453 necessary to limit the source to a single, validated, named supplier. Alternatively, the suitability of
454 different suppliers may be demonstrated with in vitro data for finished medicinal product manufactured
455 with different batches from each source. If these conditions are met, the omission of the relevant
456 specification criteria, other than particle size distribution (if relevant), can be justified based on data.

457 4.2.4.1. Pharmacopoeial excipients

458 Excipients that have a well-established history of use in inhalation medicinal products and are tested
459 according to a monograph of an accepted pharmacopoeia, may be used without providing safety data
460 on the excipient alone, provided that the amounts used are common for the route of administration.

461 For any excipient without a well-established history of use in inhalation medicinal products or is used at
462 a concentration above that previously used by the inhalation route, safety must be sufficiently
463 demonstrated by providing relevant data in Module 4.

464 4.2.4.2. Non-pharmacopoeial excipients

465 For excipients not described in any pharmacopoeia appropriate specification tests and limits,
466 particularly with respect to purity, should be established and justified. Justification is not required for
467 well-known excipients which have been used in similar finished medicinal products for a long period of
468 time.

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469 Excipients that are not well-known must be demonstrated to be safe when administered by the
470 inhalation route of administration, relevant data should be provided in Module 4. In addition,
471 information on the manufacture of the excipient may also be necessary. A general outline of the
472 manufacturing and purification procedures may be sufficient.

473 4.2.4.3. Novel excipients

474 For excipients that are not used in inhalation medicinal products before, full details of manufacture,
475 characterisation and controls with cross reference to supporting safety data (provided in Module 4)
476 should be provided. The documentation on chemistry should include the origin of the excipient,
477 including the name and address of the supplier and a general outline of the manufacturing and
478 purification procedures. The chemical structure, and if appropriate morphological information, should
479 be included. Physical and chemical properties, identification and purity need to be tested by validated
480 analytical methods. Batch results and stability data should be provided.

481 4.2.5. Control of the finished medicinal product (CTD 3.2.P.5)

482 This section describes specification tests specific to inhalation medicinal products. Standard finished
483 medicinal product specification tests (e.g., identification, degradation products, pH) have not been
484 listed, but it is expected that these tests are included in the specifications, as needed. Other guidance
485 documents (e.g., ICH Q6A) should be consulted in this regard.

486 Acceptance criteria should be set based on the observed ranges of variation in batches that showed
487 acceptable performance in vivo. Process capability and stability data may also be considered. In
488 addition, different tests and limits may apply at release versus shelf-life; differences should be clearly
489 described and justified.

490 Table 4.2.2 includes the tests normally included in the finished medicinal product specifications for
491 inhalation medicinal products. Not all tests are necessary for all types of inhalation medicinal products,
492 as noted in table. 4.2.2.

Table 4.2.2. Finished medicinal product specification tests for inhalation medicinal products.

Pressurised Dry powder inhalers Preparations for

Non-
Finished medicinal metered- (DPI) nebulisation
pressurised
product dose
Device- Pre- Single- Multi- metered-dose
specification test inhalers
metered metered dose dose inhalers
(pMDI)

(a) Description Yes Yes Yes Yes Yes Yes

(b) Assay Yes Yes Yes Yes Yes Yes

(c) Moisture content Yes Yes Yes No No No

(d) Mean delivered

Yes Yes Yes No No Yes
dose

(e) Uniformity of
Yes Yes Yes No No Yes
delivered dose

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 Table 4.2.2. Finished medicinal product specification tests for inhalation medicinal products.

Pressurised Dry powder inhalers Preparations for

Non-
Finished medicinal metered- (DPI) nebulisation
pressurised
product dose
Device- Pre- Single- Multi- metered-dose
specification test inhalers
metered metered dose dose inhalers
(pMDI)

(f) Content
uniformity /
No No No Yes No No
uniformity of dosage
units

(g) Fine particle dose Yes Yes Yes Yesa Yesa Yes

(h) Leak rate Yes No No No No No

(i) Microbial /
Yes Yes Yes Yesb Yes Yes
microbiological limits

(j) Sterility No No No Yesc Yesc No

(k) Leachables Yes No No Yes Yes Yes

(l) Preservative
No No No Yesb Yesb Yesb
content

(m) Number of
deliveries per Yes Yes No No No Yes
container

493 a For suspensions.

494 b If a preservative is present.
495 c If the product is sterile.

496 4.2.5.1. (a) Description

497 A description of both the formulation and the full delivery device (including actuator, dose counter,
498 etc.) should be given where applicable. For medicinal products for nebulisation, the immediate
499 packaging should be described (e.g., translucent LDPE nebule).

500 4.2.5.2. (b) Assay

501 For multidose medicinal products, the amount of the active substance(s) should be determined per
502 weight unit or per volume unit, as applicable. For single-dose medicinal products, the assay should be
503 expressed as mass per dosage unit. At release assay limits of ±5% should apply unless otherwise
504 justified.

505 4.2.5.3. (c) Moisture content

506 The limit for moisture content should be established based on results seen in stability studies. If the
507 results are stable throughout the shelf-life of the medicinal product, or if it has been demonstrated that
508 any changes in moisture content do not result in changes to any other parameters, it may be
509 acceptable to omit this test from the specification.

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510 4.2.5.4. (d) Mean delivered dose

511 The amount of active substance in one actuation should be determined by calculating the mean of the
512 delivered dose uniformity test results (see 4.2.5.5), with corrections as necessary to convert from “per
513 dose” amounts to “per actuation” amounts. Limits of ±15% of the label claim should apply, as stated
514 in accepted pharmacopeia (e.g. Ph. Eur. monograph “Preparations for inhalation”).

515 4.2.5.5. (e) Uniformity of delivered dose

516 Uniformity of delivered dose should be ensured both within a device (intra-inhaler) and between
517 devices (inter-inhaler). The tests should be conducted according to pharmacopoeial methods, or
518 suitably validated alternatives. A single test combining intra/inter variability may be acceptable
519 provided that the test method is suitably justified and validated.

520 Limits applied should be consistent with accepted pharmacopeia, with adaption as necessary to test
521 both intra/inter device variability. The use of uniformity of weight per actuation in lieu of the uniformity
522 of the content of the delivered dose may be acceptable for solution formulations.

523 4.2.5.6. (f) Content uniformity / uniformity of dosage units

524 Content uniformity should be investigated on samples removed from the containers as per the
525 instructions provided to patients and health care professionals. Acceptance limits should be justified,
526 taking into consideration pharmacopoeial requirements.

527 The use of uniformity of weight per actuation in lieu of content uniformity may be acceptable for
528 solution formulations.

529 4.2.5.7. (g) Fine particle dose

530 The fine particle dose test should be conducted using a validated multistage impactor or impinger
531 method, or a suitably validated alternative (e.g., an abbreviated impactor method, AIM). If using an
532 abbreviated impactor, cross-validation or verification between the full resolution impactor method and
533 the abbreviated method needs to be performed. Where an abbreviated method is used for routine
534 testing, results for clinical batches using the same method should be submitted.

535 It is normally considered acceptable and preferred to set upper and lower limits on the results of
536 pooled stages corresponding to a particle size distribution of less than 5 μm as specified e.g., in Ph.
537 Eur. 2.9.18. Alternative particle size limits may be found acceptable with adequate justification. The
538 mass of the active substance(s) should be reported rather than the percentage of emitted dose (or
539 other derived parameter). Additional criteria may be appropriate such as grouped stages or limits for
540 mass median aerodynamic diameter (MMAD) and/or geometric standard deviation (GSD) if the fine
541 particle dose alone is insufficient to fully characterise the particle size distribution of the therapeutic
542 dose. Control of the particle size distribution above 5 μm may be necessary depending on the
543 relevance of this fraction for the efficacy and safety of the medicinal product.

544 In all cases, limits should be qualified by the fine particle dose results for batches used for in vivo
545 studies (pivotal clinical and/or comparative) and should be reported on a per actuation or per dose
546 basis. Normally, it is considered that a specification range of up to ±25% is adequate for quality
547 control of most inhalation medicinal products, based on the manufacturing process and the variability
548 of the analytical methods. It should be taken into account that the same analytical methods are used
549 for the determination of fine particle dose concerning clinical batches as well as for the medicinal
550 product intended for the market. Ranges wider than ±25% should be sufficiently justified by in vivo
551 data. The proposed specification limits should take into account the shelf-life performance of the

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552 medicinal product. If there are differences observed compared to the medicinal product at release, the
553 clinical relevance should be discussed. A tighter specification limit at release may be required to ensure
554 acceptable medicinal product performance at end of shelf-life.

555 If there are several strengths, the specification range(s) for each of the strengths should normally not
556 be overlapping.

557 4.2.5.8. (h) Leak rate

558 A leak rate test and limits should be included in the specification.

559 4.2.5.9. (i) Microbial / microbiological limits

560 Microbiological quality testing should be conducted according to an accepted pharmacopoeial test, or
561 justification for not including this test should be included.

562 4.2.5.10. (j) Sterility

563 Sterility testing should be conducted according to an accepted pharmacopoeial test.

564 4.2.5.11. (k) Leachables

565 Depending on the results of the pharmaceutical development study on extractables and leachables,
566 and in particular the results of safety assessments (see section 4.2.2.4), a test and qualified limits for
567 leachables should be included in the specification.

568 4.2.5.12. (l) Preservative content

569 Preservative assay testing should be conducted.

570 4.2.5.13. (m) Number of deliveries per container

571 The number of deliveries per container should be demonstrated to be no less than the labelled number
572 of actuations.

573 4.2.6. Container Closure System (CTD 3.2.P.7, 3.2.R)

574 In addition to standard container closure system specification tests (e.g., identification, dimensions),
575 the specifications of the container closure system should include where applicable further tests to
576 confirm reproducible delivery of the finished medicinal product by the delivery device. For example, for
577 pMDI, specifications should include tests such as shot weight of individual sprays and actuator orifice
578 length and diameter.

579 The composition of all container closure system components should be provided and should comply
580 with relevant standards (e.g., pharmacopoeial) in relation to their intended use.

581 For multidose inhalation medicinal products the dose counter should be described.

582 For coated canisters and/or valves, the complete composition of the coating and the procedure
583 (including process controls) used in the coating process should be provided.

584 For non-compendial components, in addition to the resin used, any additives included should also be
585 described.

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586 All medical devices, including inhalers and nasal devices, have to fulfil the general requirements as
587 outlined in the Medical Device Regulation (EU) 2017/745. The device shall meet the general safety and
588 performance requirements set out in Annex I of Regulation (EU) 2017/745, which apply to it, taken
589 into account its intended purpose. For medical devices that are co-packaged with the medicinal product
590 and that are non-integral drug device combination products, evidence should be provided that relevant
591 standards have been met e.g., the dossier should include a discussion demonstrating that the GSPRs
592 have been met, EU Declaration of Conformity or NB Certificate of Conformity, or other appropriate
593 documentation. Module 3.2.R should include information related to demonstration of compliance of the
594 device with Annex I of Regulation (EU) 2017/745. Further requirements are outlined in
595 EMA/CHMP/QWP/BWP/259165/2019 “Guideline on the quality requirements for drug device
596 combination products”.

597 4.2.7. Stability (CTD 3.2.P.8)

598 All inhalation medicinal products should be tested on stability against the stability indicating tests
599 included in the finished medicinal product specification. Weight loss should also be monitored where
600 appropriate.

601 If product performance is considered to be influenced by the storage orientation (e.g., for pMDI),
602 containers should be stored in various orientations during the study in order to determine the effect of
603 orientation. Data should be presented separately for each orientation.

604 If the medicinal product includes secondary packaging in order to protect it from light and/or humidity
605 (e.g., DPI inside a foil overwrap), the length of time that the medicinal product may be used after the
606 protective packaging has been removed should be supported by an in-use stability study. These in-use
607 studies should involve removing the medicinal product from the protective packaging close to the end
608 of its shelf-life and testing the exposed medicinal product against the finished medicinal product
609 specifications. For example, if a medicinal product should be used within three months after removal of
610 the protective packaging (according to the instructions for use), the medicinal product should be
611 removed from the protective packaging three months before the end of the shelf-life and tested at the
612 end of the shelf-life.

613 Information on the use of the medicinal product once the protective packaging has been removed
614 should be provided to the patient.

615 4.3. Therapeutic equivalence

616 The quality requirements to be considered for the development of a medicinal product which is
617 intended to be authorised by an abridged application are not different from the development of the
618 inhalation medicinal product used as a reference medicinal product. Quality data requirements as
619 described in this guideline should be met, supplemented by appropriate comparative quality and
620 clinical data with respect to the chosen reference medicinal product.

621 For inhalation medicinal products comparative in vitro data between the abridged application medicinal
622 product and the reference medicinal product must be provided. The pharmaceutical criteria for
623 demonstrating therapeutic equivalence as described in Guideline on the requirements for
624 demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and chronic
625 obstructive pulmonary disease (COPD) (CPMP/EWP/4151/00) should be considered even though the
626 product will be used for other indications than asthma or COPD.

627 If no in vivo studies are performed, any specification limits for relevant parameters, e.g., aerodynamic
628 particle size distribution) for the finished product and particle size for the excipients, must be based on
629 the batches used for substantiation of in vitro equivalence.

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630 Development of a pMDI should always include testing with at least one specific spacer or holding
631 chamber appropriate for the intended patient population (e.g., paediatrics, adults when there may be a
632 need to facilitate administration of the relevant dose). If a spacer is recommended in the SmPC of the
633 reference medicinal product, this spacer should be used for comparison. Studies required to
634 demonstrate therapeutic equivalence are described in the multidisciplinary guideline for OIP
635 (CPMP/EWP/4151/00).

636 4.4. Product information

637 Besides the general requirements, some specific information for inhalation medicinal products needs to
638 be included in the Summary of Product Characteristics (SmPC) and the Package Leaflet (PL).

639 - Name of the medicinal product: In accordance with the QRD recommendations on the expression
640 of strength in the name of centrally authorised human medicinal products (EMA/707229/2009),
641 the strength should be expressed as the amount per delivered dose (ex-actuator). The principle
642 to use metered dose (ex-valve) may be applicable in some specific cases. For example, if the
643 approved reference medicinal product has a strength expressed as metered dose, it is strongly
644 recommended that the product (i.e. an abridged application of that reference medicinal product)
645 applies the same principle.

646 - Qualitative and quantitative composition: For clarity, both the amount per delivered dose and
647 metered dose should be declared. The principle used for expression of strength should be stated
648 first.

649 - Administration and handling: Relevant instructions for the correct administration and handling
650 should be clearly described including directions with respect to the following items (if
651 applicable):

652  shaking requirements

653  the need for priming and re-priming

654  the effect of flow rate on the performance of the product

655  orientation of the inhaler during inhalation

656  the use of spacer/holding chamber

657  the cleaning requirements of the device and its components should be included.

658  for products for nebulisation the nebuliser system(s) and settings that were proven to
659 be effective and safe in vivo must be indicated, including information on the droplet
660 size distribution, delivery rate of the active substance and total active substance
661 delivered.

662 - Excipients: If lactose is an excipient from bovine origin the relevant warning for cow’s milk
663 protein in accordance with the guideline on Excipients should be included.

664 For inhalation powders in hard capsules the capsule shell is considered as an excipient and the
665 components should be stated under a separate subheading “Capsule shell”.

666 - Special precautions for storage: for pMDI the following statement should be included: “The
667 canister contains a pressurised liquid. Do not expose to temperatures higher than 50°C. Do not
668 pierce the canister.” Temporary storage deviations, such as temperatures below or above the
669 recommended range, should be described.

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670 - Nature and contents of container: The type of the device and its components should be listed. A
671 visual description of the inhaler device should be included.

672 4.5. Lifecycle management

673 Inhalation products, in particular DPI and pMDI, are considered as specialised pharmaceutical forms, in
674 respect to the current guideline on process validation (EMA/CHMP/CVMP/QWP/BWP/70278/2012 Rev.
675 1). Exemption from a non-standard manufacturing process may be accepted if adequately justified by
676 the manufacturer, on a case-by-case basis, as described in the above-mentioned guideline.

677 For any proposed change, a risk assessment should be performed to determine its impact on quality,
678 safety or efficacy of the product. The following changes may be considered to have a significant
679 impact:

680 - Change in the physicochemical state and/or thermodynamic activity of the active substance.

681 - Change in the qualitative and/or quantitative composition of excipients.

682 - Change in the geometry or material of the device or device components.

683 - Change of suppliers in device and/or spacer devices for pMDI or nebulisers.

684 - Change in the manufacturing process, e.g.:

685  Change in a single Critical Process Parameter.

686  Changes in a number of non-Critical Process Parameters.

687 - Change in batch size.

688 - Any other change that affects the in vitro APSD or in vitro dissolution release characteristics of
689 the finished product.

690 It should be noted that the list is not exhaustive, and depending on the product characteristics other
691 changes might also have a significant impact. In all cases, the change should be supported by
692 appropriate and representative batch data for all critical quality attributes before and after the
693 proposed change. In addition, in vivo studies may also be required, unless otherwise justified.

694 5. Nasal medicinal products

695 Inhalation and nasal medicinal products have many similarities and therefore, most of the
696 requirements specified for inhalation medicinal products in section 4 also apply for nasal medicinal
697 products. One difference between inhalation and nasal medicinal products is the desired
698 particle/droplet size of the finished medicinal product. For inhalation medicinal products the
699 particles/droplets need to be in the respirable size (i.e., <5 µm) while for nasal medicinal products
700 these small particles may reach the lung and give unwanted effects. Only requirements and
701 characteristics unique for nasal medicinal products are specified in this section.

702 5.1. Active substance (CTD 3.2.S)

703 The requirements are similar as described for inhalation medicinal products, see section 4.1.

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704 5.2. Finished medicinal product (CTD 3.2.P)

705 5.2.1. Description and composition of the finished medicinal product (CTD
706 3.2.P.1)

707 The complete qualitative and quantitative composition should be specified including any excipient (e.g.,
708 solvents, gasses) removed during manufacturing. The amount should be expressed in concentration
709 (i.e., amount per unit volume or weight), as well as amount per container and per spray or drop,
710 where applicable.

711 The primary packaging, type of device and, if necessary, the secondary packaging or other
712 components required for reasons of stability should be described. A detailed description of the
713 packaging should be included in Module 3.2.P.7.

714 5.2.2. Pharmaceutical development (CTD 3.2.P.2)

715 See section 4.2.2.

716 The tests indicated in Table 5.2.1 are normally conducted to characterise nasal medicinal products. Not
717 all tests are necessary for all types of nasal medicinal products. The pharmaceutical development
718 studies should be performed as discussed below and in section 4.2.2. Tests for fine particle dose are
719 not relevant for nasal medicinal products.

Table 5.2.1. Pharmaceutical development studies for nasal medicinal products.

Nasal liquids

Pressurised Nasal Non-

Pharmaceutical
metered- powders, Single- Single- pressurised
development Multidose
dose nasal device- dose dose multidose
study drops
spray metered drops spray metered-
dose spray

(a) Physical
Yesa Yes Yesa Yesa Yesa Yesa
characterisation

(b) Minimum fill

Yes Yes Yes Yes Yes Yes
justification

(d) Extractables /
Yes No Yes Yes Yes Yes
leachables

(f) Particle /
droplet size Yes Yes No No Yes Yes
distribution

(g) Uniformity of
delivered dose
Yes Yes No No No Yes
through container
life

(j) Actuator /
mouthpiece Yes Yes No No Yes Yes
deposition

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 Table 5.2.1. Pharmaceutical development studies for nasal medicinal products.

Nasal liquids

Pressurised Nasal Non-

Pharmaceutical
metered- powders, Single- Single- pressurised
development Multidose
dose nasal device- dose dose multidose
study drops
spray metered drops spray metered-
dose spray

(l) Shaking
Yesa No Yesa Yesa Yesa Yesa
requirements

(m, n) Initial &

re-priming Yes No No No Yes Yes
requirements

(o) Cleaning
Yes Yes No Yes No Yes
requirements

(p) Low
temperature Yes No No No No No
performance

(q) Performance
after temperature Yes No No No Yes Yes
cycling

(r) Effect of
environmental Yes Yes No No No No
moisture

(s) Robustness Yes Yes Yes Yes Yes Yes

(t) Delivery
device Yes Yes Yes Yes Yes Yes
development

(u) Preservative
effectiveness / No No Nob Yesc Nob Yesc
efficacy

(x) Spray pattern

Yes Yes No No Yes Yes
/ plume geometry

720 a For suspensions.

721 b Single use formulations should preferably be preservative free, but if a preservative is present it
722 should be adequately justified.
723 c If a preservative is present.

724 5.2.2.1. (a) Physical characterisation

725 The requirements are generally similar as described for inhalation medicinal products, see section
726 4.2.2.1. For nasal medicinal products rheological characterisation (e.g., thixotropy, viscosity), surface
727 tension and density may also be relevant.

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728 5.2.2.2. (f) Particle / droplet size distribution (CTD 3.2.P.2.4)

729 The particle or droplet size distribution is considered as one of the CQAs of nasal medicinal products. It
730 is therefore important to fully characterise the distribution during the development and ensuring
731 consistency with the commercial product.

732 Testing should be conducted using a suitable method (e.g., laser diffraction or multistage cascade
733 impactor with settings adjusted for nasal use). It should be demonstrated that deposition of the
734 medicinal product is localised in the nasal cavity, i.e., by demonstrating that the vast majority of the
735 particles/droplets are larger than 10 µm as measured by cascade impaction (e.g., abbreviated
736 impactor).

737 5.2.2.3. (u) Preservative effectiveness / efficacy (CTD 3.2.P.2.5)

738 For products containing a preservative a study should be conducted to demonstrate the
739 effectiveness/efficacy of the preservative. Single-dose formulations for nasal use should be
740 preservative free. In some cases, an excipient could have several different functions, e.g., a
741 preservative and solubilising agent. If preservatives are used in the formulation their presence should
742 be adequately justified, and the minimum content limit should be demonstrated as microbiologically
743 effective.

744 5.2.2.4. (x) Spray pattern / plume geometry (CTD 3.2.P.2.4)

745 Spray pattern and plume geometry should be studied to characterise the performance of the complete
746 finished medicinal product, i.e., the formulation in combination with the pump. Both size and shape
747 should be evaluated. The characteristics may be used to ensure consistency during development and
748 as a baseline for comparison with a reference medicinal product or for future variations to an approved
749 product.

750 5.2.3. Manufacture (CTD 3.2.P.3)

751 A detailed description of the manufacturing process for the finished medicinal product, including filling
752 and packaging, should be included. If the active substance(s) or any excipient is micronised after being
753 received from the supplier, the micronisation process should be described. Nasal medicinal products
754 are in general considered to be manufactured by standard manufacturing processes. In some cases,
755 the finished medicinal product may be considered complex (e.g., suspensions or low active substance
756 content) as described in the guideline on process validation (EMA/CHMP/CVMP/QWP/BWP/ 70278/2012
757 Rev1). Module 3.2.P.3.3 and 3.2.P.3.4 should be sufficiently detailed and include both critical and non-
758 critical process parameters justified by reference to the manufacturing process development
759 undertaken.

760 The controls for critical steps and intermediates should be described. Appropriate in-process controls
761 should be established based on CQAs and CPPs determined during the development studies, e.g.,
762 assay, homogeneity, osmolality, pH, viscosity, consistency of filling, quality of sealing.

763 The manufacturing process should be validated to ensure the homogeneity of the formulation
764 throughout the filling process during routine production and include controls assuring that all
765 containers are within an appropriate fill volume or fill weight range, and that the closure system is
766 applied correctly.

767 5.2.4. Control of excipients (CTD 3.2.P.4)

768 The requirements are similar as described for inhalation medicinal products, see section 4.2.4.

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769 5.2.5. Control of the finished medicinal product (CTD 3.2.P.5)

770 This section describes specification tests specific to nasal medicinal products. Standard finished
771 medicinal product specification tests (e.g., identification, degradation products, pH, viscosity) have not
772 been included, but it is expected that these tests be included in the specifications. Other guidance
773 documents (e.g., ICH Q6A) should be consulted in this regard.

774 Acceptance criteria should be set based on the observed ranges of variation in batches that showed
775 acceptable performance in vivo, process capability and stability data may also be considered. In
776 addition, different tests and limits may apply at release versus shelf-life; differences should be clearly
777 described and justified.

778 Table 5.2.2 includes the tests normally included in the finished medicinal product specifications for
779 nasal medicinal products. Not all tests are necessary for all types of nasal medicinal products, as noted
780 in table 5.2.2. The tests are discussed below and in section 4.2.5.

Table 5.2.2. Finished product specification tests for nasal medicinal products.

Nasal liquids

Pressurised Nasal Non-

Finished product metered- powders, Single- pressurised
specification test dose nasal device- Multidos Single-
dose multidose
spray metered e drops dose spray
drops metered-
dose spray

(a) Description Yes Yes Yes Yes Yes Yes

(b) Assay Yes Yes Yes Yes Yes Yes

(c) Moisture
Yes Yes No No No No
content

(d) Mean delivered

Yes Yes No Yes No Yes
dose

(e) Uniformity of
Yes Yes No Yes No Yes
delivered dose

(f) Content
uniformity /
No No Yes No Yes No
uniformity of
dosage units

(h) Leak rate Yes No No No No No

(i) Microbial /
microbiological Yes Yes Yesa Yes Yesa Yes
limits

(j) Sterility No No Yesb Yesb Yesb Yesb

(l) Preservative
No No No Yesa No Yesa
content

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 Table 5.2.2. Finished product specification tests for nasal medicinal products.

(m) Number of
deliveries per Yes Yes No No No Yes
container

(n) Particle /
droplet size Yes Yes No No Yes Yes
distribution

781 a If a preservative is present.

782 b If the product is sterile.

783 5.2.5.1. (n) Particle / droplet size distribution

784 Limits should be included for an allowed range for the median diameter and on the sub 10 µm particles
785 / droplets. The sub 10 µm particles / droplets should be tested using a validated method (e.g., cascade
786 impaction or an abbreviated impactor with settings adjusted for nasal use or, for solutions, laser
787 diffraction). The median diameter can be tested with a validated laser diffraction method. The limits
788 should be qualified by the results of batches used for in vivo studies (pivotal clinical and/or
789 comparative), or in case therapeutic equivalence has been substantiated by in vitro testing only, the
790 test batches that have been used in the in vitro comparison.

791 5.2.6. Container closure system (CTD 3.2.P.7)

792 The requirements are similar as described for inhalation medicinal products, see section 4.2.6.

793 5.2.7. Stability (CTD 3.2.P.8)

794 The requirements are similar as described for inhalation medicinal products, see section 4.2.7.

795 5.3. Therapeutic equivalence

796 The quality requirements to be considered for the development of a medicinal product which is
797 intended to be authorised by an abridged application are not different from the development of the
798 nasal medicinal product used as reference medicinal product. Quality data requirements as described in
799 this guideline should be met, supplemented by appropriate comparative quality and clinical data with
800 respect to the chosen reference medicinal product.

801 For nasal medicinal products claiming essential similarity to a reference medicinal product, studies
802 required to demonstrate therapeutic equivalence may depend on the intended site of action of the
803 active substance(s), local or systemic effect. Note for Guidance on the clinical requirements for locally
804 applied, locally acting products containing known constituents (CPMP/EWP/239/95) and Guideline on
805 the investigation of bioequivalence (CPMP/EWP/QWP/1401/98) may be consulted.

806 In order to conclude in vitro therapeutic equivalence, the following parameters should be considered in
807 the comparison between test and reference product, when relevant:

808 - Qualitative and quantitative composition

809 - Actuation volume, single actuation content, or mass of single dose

810 - Droplet size distribution

811 - Mass of droplets smaller than 10 µm

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812 - Particle size distribution and morphological form of active substance for suspensions

813 - Spray pattern / plume geometry

814 - Rheological properties (e.g., thixotropy, viscosity)

815 - Surface tension

816 - pH

817 - Density

818 - Osmolality

819 - Buffer capacity

820 Other parameters may be applicable depending on the finished medicinal product characteristics. The
821 chosen and omitted parameters should be discussed and justified. The in vitro equivalence should be
822 performed and evaluated based on a predefined study protocol including methods of comparison and
823 acceptance criteria. Any differences should be accompanied by a rationale as to why the differences
824 will not result in different deposition and/or absorption characteristics.

825 5.4. Product information

826 Besides the general requirements, some specific information for nasal medicinal product needs to be
827 included in the Summary of Product Characteristics (SmPC) and the Package Leaflet (PL).

828 - Name of the medicinal product: In accordance with the QRD recommendations on the expression
829 of strength in the name of centrally authorised human medicinal products (EMA/707229/2009),
830 the strength should be expressed as the amount per unit volume (e.g. mg/mL), preferably in
831 terms of the active moiety.

832 - Qualitative and quantitative composition: For nasal drops the amount per drop should be stated.

833 - Administration and handling: Relevant instructions for the correct administration and handling
834 should be clearly described, including directions with respect to the following items (if
835 applicable):

836  shaking requirements

837  the need for priming and re-priming

838  orientation of the nasal device

839  the cleaning requirements of the device and its components

840 - Excipients: If lactose is an excipient from bovine origin the relevant warning for cow’s milk
841 protein in accordance with the guideline on Excipients should be included.

842 -

843 - Special precautions for storage: For pressurised metered-dose nasal sprays the following
844 statement should be included: “The canister contains a pressurised liquid. Do not expose to
845 temperatures higher than 50°C. Do not pierce the canister.” Temporary storage deviations, such
846 as temperatures below or above the recommended range, should be described.

847 - Nature and contents of container: The type of the device and its component materials should be
848 listed. A visual description of the device should be included.

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849 5.5. Lifecycle management

850 For any proposed change, a risk assessment should be performed to determine its impact on quality,
851 safety or efficacy of the medicinal product. The following changes may be considered to have a
852 potential significant impact:

853 - Change in the physicochemical state and/or thermodynamic activity of the active substance(s).

854 - Change in the qualitative and/or quantitative composition of excipients.

855 - Change in the geometry or material of the device or device components.

856 - Change of suppliers in device.

857 - Change in the manufacturing process, e.g.:

858  Change in a single Critical Process Parameter.

859  Changes in a number of non-Critical Process Parameters.

860 - Any other change that affects the particle/droplet size distribution, spray pattern or plume
861 geometry.

862 Please note that the list is not exhaustive, depending on the medicinal product characteristics other
863 changes might also have a significant impact. In all cases, the change should be supported by
864 appropriate and representative batch data for all critical quality attributes before and after the
865 proposed change. In addition, in vivo studies may also be required, unless otherwise justified.

866

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867 Definitions
Activation: The act of setting in motion the delivery device.

Actuation: The release of active substance from the delivery device by a single
activation (e.g., mechanical or breath).

Container closure The sum of packaging components that together contain and protect the
system: dosage form. The container closure system may serve as a delivery device.

Delivered dose: The quantity of active substance that is available to the user, ex-device, on
a per dose basis.

Delivery device: The sum of component(s) of the container closure system responsible for
delivering the active substance to the respiratory tract (inhalation medicinal
product) or the nasal and/or pharyngeal region (nasal medicinal product).

Dose: Quantity of the active substance to be administered at one time, as

specified in the product information; also, the number of actuations
providing that quantity of active substance. One dose may consist of
several actuations.

Dosing interval: The recommended length of time between doses, as specified in the
product information.

Dry powder inhaler An inhalation medicinal product containing a reservoir of powder which is
(DPI), device- measured into individual actuations by the delivery device.
metered:

Dry powder inhaler An inhalation medicinal product containing pre-measured actuations,

(DPI), pre-metered: usually in capsules or blister packaging.

Ex-actuator: Not including the quantity of active substance deposited on the actuator.

Extractables: Compounds which may be extracted from the container closure system by
using stressful conditions.

Fine particle dose: The quantity of active substance in an inhalation medicinal product that is
generally considered to be of a size capable of penetrating the lung during
inhalation (approximately 5 μm and smaller), on a per actuation or per
dose basis.

Geometric standard Derived from the plot of the cumulative percentage of mass less than the
deviation (GSD): stated cut-off diameter versus the cut-off diameter by the equation:
(D84.13% / D15.87%)½

Holding chamber: An add-on device (spacer) for use with a pressurised metered-dose inhaler
(pMDI) consisting of a reservoir with an inhalation valve to retain the
aerosol until inhalation by the patient. It may also have an exhalation valve
to prevent the patient from breathing into the reservoir.

Inhalation A finished medicinal product (including the delivery device, where

medicinal product: applicable) whose intended site of deposition is the respiratory tract. The
site of action may be local or systemic.

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 Label claim: The amount of active substance (usually on a per actuation basis) declared
on the label of the medicinal product.

Leachables: Compounds which may leach from the container closure system into the
formulation under normal conditions of storage and use.

Metered dose: The quantity of active substance contained in the delivery device metering
chamber.

Mass median The diameter of a sphere of unit density having the same terminal settling
aerodynamic velocity as the particle at issue; derived from the plot of the cumulative
diameter (MMAD): percentage of mass less than the stated cut-off diameter versus the cut-off
diameter by determination of the diameter at 50.00%.

Minimum delivered The smallest recommended dose according to the product information,
dose: expressed as delivered dose.

Nasal medicinal A finished medicinal product (including the delivery device, where
product: applicable) whose intended site of deposition is the nasal and/or pharyngeal
region. The site of action may be local or systemic.

Nebuliser: A device used to continuously atomize liquids for inhalation.

Non-pressurised Portable, inhalation delivery device containing an aqueous solution,

metered-dose suspension or emulsion, which delivers one dose in one (or more)
inhaler: actuation(s).

Non-pressurised Portable, nasal delivery device containing an aqueous solution, suspension

metered-dose nasal or emulsion, which delivers one dose in one (or more) actuation(s).
spray:

Plume geometry: Spray characteristics determined by the spray angle and plume width.

Pressurised An inhalation medicinal product containing one or more propellants in a

metered-dose pressurised delivery device.
inhaler (pMDI):

Pressurised Medicinal product for nasal administration containing one or more

metered-dose nasal propellants in a pressurised delivery device.
spray:

Preparations for A liquid inhalation medicinal product administered via a commercially

nebulisation: marketed nebuliser.

Spacer: An add-on device for use with a pressurised metered-dose inhaler (pMDI)
consisting of a reservoir into which the aerosol is dispensed.

Spray: See actuation.

Spray pattern: Spray characteristics determined by size and shape.

Target delivered The quantity of active substance expected to be released from the device in
dose: the number of actuations equivalent to a dose.

Target delivery The quantity of active substance expected to be released from the delivery
amount: device (i.e., ex-actuator or ex-device) in one actuation.

868

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